GSK ‘real world’ study offers new model for drug trials
Pharma groups look to evidence in normal medical settings to prove value for money
GlaxoSmithKline has conducted the world’s first drug trial under “real world” conditions — closely watched by an industry under greater pressure than ever to prove the value of its medicines to cost-constrained health systems.
In a global first for drugmakers, GSK obtained permission to test Relvar, a drug to treat asthma and chronic obstructive pulmonary disease (COPD), before it had received full regulatory approval. It did this by setting in place an electronic patient data-monitoring system that ensured any adverse reactions were immediately communicated to physicians.
Martin Gibson, a University of Manchester professor and senior diabetes doctor, led the team that devised the technology underpinning the trial — linking primary care, hospitals and pharmacies in Salford, Greater Manchester. He said he has been contacted by “dozens” of companies including some of the pharmaceutical industry’s biggest names, planning to carry out their own trials using the same Salford database.
Some are about to get under way, Prof Gibson added, although he refused to name the companies involved because of commercial confidentiality.
GSK carried out the four-year trial under the everyday conditions of general practice in Greater Manchester. On Friday the city announced discussions are under way over further such collaborations, with the goal of securing better value for money from its £1bn annual spend on medicines.
The group advertised for recruits, and almost any COPD patient, however elderly or sick, could take part. In a striking departure from conventional practice, doctors were able to take patients off Relvar, mid-trial, if they believed another treatment would work better — without the patients being removed from the study.
As the healthcare landscape shifts, particularly in the US, the traditional sales model, with drugs sold directly to individual physicians, is becoming less prevalent. Now drugmakers must often convince a wider array of stakeholders, including insurers and hospitals, that their medicines represent value for money.
Patrick Vallance, president for research and development at GSK, acknowledges that some, even inside the company, initially had doubts about the study. “People said ‘who really cares what happens in one place in the north of England?’, and ‘nobody in the US is going to pay any attention to it’.”
In fact, he says, the US Food and Drug Administration and other bodies, such as the National Academy of Sciences, “are paying a lot of attention to it . . . as they look at how you set up systems to be able to generate so-called real world evidence”.
Enhancing the commercial case for gleaning evidence in normal medical settings, the 21st Century Cures Act, among the last passed under the Obama administration, potentially allows a company to gain approval for a new application for a drug by submitting real world evidence, without the need for a traditional clinical trial.
Andrew Baum, global head of healthcare research at Citigroup, says: “Real world data are definitely taking on a greater importance.”
GSK is heavily dependent on the revenues from its respiratory franchise. Total sales at its pharmaceuticals business in 2016 were £16.1bn, of which respiratory accounted for £6.5bn, or about 40 per cent.
But Advair, an asthma treatment that has long been one of its blockbuster products, lost patent protection in the US in 2010 and a generic replacement is awaiting approval from the US FDA. Relvar, marketed in the US as Breo, is one of a stable of drugs on which the company is relying to offset lost revenue. Sales of Relvar stood at £620m last year — compared with about £3.5bn for Advair.
The key insight GSK gained from the study was that Relvar, an inhaler used once a day, cut incidences of acute symptoms such as severe breathing problems by more than 8 per cent, compared with rival drugs.
The reduction appeared to reflect the fallibility of patients who often forget to take medication or do not follow instructions — so that a once-daily medicine in place of a twice-a-day drug in itself improved outcomes. The Salford study captured this in a way that would not have been possible in a traditional trial in which patients would have been carefully monitored to ensure medicines were taken exactly as prescribed, Dr Vallance suggests.
He acknowledges that the trial was “pretty high-risk”, given that the drug was being tested against alternatives with “essentially an identical mechanism of action”. He says, “normally you’d expect that experiment to answer ‘there’s no difference’, but it did answer ‘different’ because of the way it was taken, probably”.
Arguably, however, the key prize for those who hold the purse strings is whether drugs relieve strain on the wider health system, by reducing expensive hospitalisations, for example. Initial evidence from the trial, however, showed no significant reduction in the number of COPD sufferers seeking help from family doctors, or needing hospital treatment.
Indeed the number visiting GPs with non-respiratory symptoms rose in the first few weeks. Dr David Leather, global medical affairs leader for GSK’s respiratory franchise, attributes this to what might otherwise have seemed unconcerning ailments being linked in patients’ minds to the drug, as they underwent a “familiarisation period” with a new medicine.
Mr Baum argues the nature of the trial was far more striking than the specific outcome achieved.
While it was “useful and interesting” for GSK to pilot a commercial model that was likely to be used more widely by drugmakers, it had added little in the way of information about the efficacy of Relvar, he says.
“The data’s not terribly compelling, given how cheap the alternative therapies are,” he says.
However, Hilary Thomas, chief medical adviser at KPMG, the professional services company, says a reduction of 8 per cent is highly significant in such a crowded field. Many companies would have been too risk-averse to have undertaken the trial when its outcome was so uncertain, she adds.
“Translate that [reduction] in a growing condition for an ageing population and the savings are enormous. A change of even 8 per cent scaled up could free up hospital beds.”
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Beryl Howard attributes her health problems to a bleak day, more than 50 years ago, when she had to walk miles home in a suffocating smog in Manchester.
The 81-year-old, a participant in GSK’s Relvar trial, traces the eventual onset of chronic obstructive pulmonary disease to that occasion. “When I arrived home, I was black from head to toe . . . The next day, I couldn’t speak. It was three days before I got my voice back. My chest has never been the same since,” she says.
As the global population ages, COPD is becoming one of the leading causes of ill health — making it a large prize for drugmakers that can develop a widely adopted treatment.
Mrs Howard — who also suffers from high blood pressure and cholesterol, conditions that might have seen her excluded from a regular study — was recruited by her GP.
Dr David Leather, who led the study, explains that a traditional trial is a bit like having an animal in a zoo: “They are under control, under observation, you know what’s going on. We wanted to create a situation where it was like a lion on safari, where the patients and the doctors did what they usually did and the only thing we were doing was changing the medicine.”
Eventually more than half the COPD patients in Salford were recruited, an unusually high level of penetration for a drug trial. The vast majority of them remained on it for its entirety. At just 7 per cent the attrition rate was far lower than the average drop out rate in a normal double-blind, randomised control trial which stands at between 20 and 30 per cent.
This may partly reflect the unobtrusive nature of the trial. Information on any health problems was communicated immediately to the team of drug investigators via electronic alerts so patients themselves were required only to undergo quarterly reviews.
Dr Naresh Kanumilli, GP in a practice that had about 100 patients in the trial, said he offered patients two reasons for joining it: the chance for extra reviews of their condition as a side-benefit of participation, and the opportunity to do “something that might benefit the population, so you could almost put your name to something”. He adds that “surprisingly the number of people wanting to do it for that reason [was greater] than for the other”.
